Abstract

Background: Aberrant PI3K and AKT signaling play an important role in the development of some human tumors by promoting cell proliferation and survival. Inhibitors that target the kinase activity of PI3K or AKT may constitute an effective treatment for human malignancies that rely on these molecules for their growth. GlaxoSmithKline has developed a PI3K inhibitor, GSK1059615, and a pan‐AKT inhibitor, GSK690693. Since AKT is activated by PI3K via generation of PIP3, and is a key effector of PI3K signaling, a high degree of overlap is expected in the effects of a PI3K and an AKT inhibitor. To determine whether the effects of the PI3K inhibitor are mediated solely through the AKT pathway, we compared the molecular response of BT474 human breast cancer cells to both GSK1059615 and GSK690693 as well as the sensitivity profile of 16 other human cancer cell lines.

Methods: The mechanisms of action of the PI3K inhibitor GSK1059615 and the AKT inhibitor GSK690693 were evaluated in BT474 human breast cancer cells using RNA expression and phosphoproteomic data. Causal Network™ Modeling was used to characterize these data sets to identify processes that contribute to the inhibition of proliferation observed in cells sensitive to these inhibitors, and processes that could explain differences in sensitivity to the two inhibitors. The sensitivity/resistance profile of 16 human cancer cell lines to GSK1059615 and GSK690693 was also determined.

Results: Four common processes were found in BT474 cells treated with either GSK690693 or GSK1059615: RB1‐Mediated Cell Cycle Arrest

Conclusions: In BT474 cells, GSK690693 and GSK1059615 inhibit cell proliferation by increasing RB1‐mediated cell cycle arrest, increasing FOXO signaling, decreasing MYC signaling, and decreasing cellular metabolism, as identified by Causal Network™ Modeling. In addition to these four shared mechanisms, the PI3K inhibitor GSK1059615 attenuates MAPK signaling. Five of 16 cell lines tested for sensitivity to the inhibitors were sensitive to GSK1059615 treatment only, and these five cell lines were the only ones that contained mutations activating MAPK signaling. Thus decreased MAPK signaling is likely an additional mechanism by which GSK1059615 inhibits cell proliferation, and may confer sensitivity to this PI3K inhibitor in cells resistant to the AKT inhibitor.